Estrogen receptor β ligands: Recent advances and biomedical applications

Abstract Recent work elucidating the role that the estrogen receptor β (ERβ), a member of the nuclear receptor superfamily, plays in regulating various physiological functions has highlighted the potential of this receptor subtype as a therapeutic target for several pathologies. In fact, molecules that are able to selectively activate ERβ hold promise for the treatment of certain cancers, as well as endometriosis, inflammatory diseases including rheumatoid arthritis, and cardiovascular and CNS conditions. Nevertheless, ERβ remains a challenging target because its ligand‐binding cavity is very similar to that present in ERα, and this makes it difficult to develop ligands having sufficient levels of ERβ selectivity for therapeutic use. Nevertheless, considerable advances have recently been made in developing both nonsteroidal and steroidal ERβ‐selective agonists. These molecules constitute not only important tools to probe the biological effects of the selective stimulation of ERβ, but some of them appear to be agents with considerable therapeutic potential. This study provides a detailed review of selective ERβ ligands that have been developed recently. After a brief introduction to the structure and nature of the two ERs and the biology of ERβ and its isoforms, the ligands are classified on the basis of their structures and activities. Common pharmacophore elements are highlighted throughout the description of the various chemical classes analyzed, and these elements are presented in a concluding summary overview along with a discussion of potential therapeutic applications of these agents in biomedicine. © 2009 Wiley Periodicals, Inc. Med Res Rev, 31, No. 3, 364–442, 2011